Pharma Manufacturing

Equipment manufacturers are developing production and packaging systems designed specifically to increase productivity while maintaining quality and reducing costs.

Several recent trends in the pharmaceutical industry are converging to squeeze profit margins for drug manufacturers, who are adopting multiple strategies in response. Increasing production efficiency is one key approach, and equipment manufacturers have been responding with the development of production and packaging systems designed specifically to increase productivity while maintaining quality and reducing costs. In biopharmaceutical manufacturing, the adoption of single-use equipment for both upstream and downstream processes at increasingly larger scales and the introduction of equipment designed for integrated continuous manufacturing are two examples.
For small-molecule manufacturing, significant progress has also been made in…

Full Name: Piezo Gripper
Team: ParkerStatus: Ready to fill demanding light-touch gripping roles
Debut: January 2015
Field Position: Robotic applications manipulating delicate discrete items safely
Skill Set: Gentle handling of small-scale discrete and fragile items
Performance Stats:• Piezo technology is rugged, offering a lifespan of up to 500,000,000 cycles, compared to others rated at 5,000,000 cycles• Maximum gripping force is 1.235 Newtons, and because the power source is electromechanical rather than pneumatic, the added expense of compressed air is avoided• Device is particularly suitable for processes that are neither nano nor macro, but somewhere in between
Regulatory Profile: Appropriate for cGMP…

Pharma can take inspiration from industries with mature quality systems and advanced quality capabilities

Quality has a special meaning in pharmaceuticals, where production or distribution errors can jeopardize human life. But other industries face similar challenges, and some have developed sophisticated quality systems. As pharmaceutical companies look for ways to improve their quality practices and performance, they can take ideas from these quality leaders and adapt them for pharma.
Quality can be defined in various ways, from “fitness for purpose” to “meeting customer expectations” to predictability in statistical terms. Each industry understands quality differently, and priorities depend on the specifics of products and markets. In the automotive industry, for instance, companies generally define quality as the ability to meet…

For the first time in a long time, the Internet is abuzz with something that might actually eclipse the Internet in terms of impact on the world.

Buzzwords get a bad rap. This is mostly due to operator error. Sometimes really valid concepts get haphazardly tossed around so frequently by people who don’t fully understand them that the actual concept starts getting muddled. But this shouldn’t always devalue the initial idea.
The “Internet of Things” is a good example. There are so many articles casually using the acronym “IoT” that it has become difficult to find a basic discussion of the concept.
In its most simplistic form, the IoT is a network of physical devices embedded with sensors and electronics, where all the devices speak to each other using the existing Internet infrastructure. The INDUSTRIAL Internet of Things (IIoT) is simply the Internet of Things when…

Based on the FDA's comprehensive review of new safety information, the agency is strengthening an existing label warning that NSAIDs increase the chance of a heart attack or stroke.

Based on the FDA's comprehensive review of new safety information, the agency is strengthening an existing label warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the chance of a heart attack or stroke. FDA is requiring updates to the drug labels of all prescription NSAIDs.
Per the FDA, prescription NSAID labels will be revised to reflect the following information:
• The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.• The risk appears greater at higher doses.• It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk for heart attack or stroke is…

The optimization and scale-up of wet granulation processes is often an essential step in the commercialization of oral solid dosage (OSD) products. Granulation enables the preparation of an optimized blend for tableting in which small quantities of highly potent active ingredients (APIs) are stably and homogeneously distributed. Furthermore, granule properties can be manipulated to control, for example, the flowability of the blend and its compressibility. In these ways granulation underpins the manufacture of high-quality tablets with consistent dose uniformity.Wet granulation, and in particular high shear wet granulation, is the technology of choice for many OSD production processes. Compared with alternative methods, high shear…

Dramatic changes in the pharmaceutical and biopharmaceutical landscape over the past decade have reshaped manufacturers' equipment and technology needs and purchasing patterns. The leading trends driving the transformation include the changing pharmaceutical pipeline, the shift to overseas manufacturing sites, new regulatory guidelines calling for use of the latest technologies to improve quality and efficiency, and a significant increase in outsourcing. Compounding these changes are continuous pressures to cut costs, improve efficiency, elevate quality and boost productivity. Together, these trends have had a significant impact on equipment and technology acquisition strategies.
What are purchasing and operations managers seeking today…

Instrument and PAT vendors are continually innovating, and 2015 is no different

Process Analytical Technology (PAT) and instrument vendors are continually advancing the usability, reliability, accuracy and efficacy of their technologies, and the first half of 2015 is no different. Companies in this sector introduced technological advancements and other innovations to better support lab and QA/QC operations.
When it comes to demonstrating new analytical equipment to the industry, PittCon has traditionally been a primary launching point for introducing PAT systems and innovations to the industry. Several vendors brought out new systems or introduced significant new features at the conference.
SPECTROSCOPYIn the world of PAT/QbD, spectroscopy occupies a leading role. One instrument that should interest physical chemistry…

New xCELLigence RTCA CardioECR is the first platform for simultaneous measurement of Cardiomyocyte Contractility and Electrophysiology

Responding to the need for more predictive preclinical assays for cardiac liability, ACEA Biosciences introduced a “ground-breaking” device the company describes as “next generation.” Designated the xCELLigence RTCA CardioECR System, it is…

From tablet marking to quality assurance, lasers and machine vision are boosting functionality and efficiency

In the multidisciplinary pharmaceutical industry, photonics plays an increasingly crucial role in the manufacturing process. From quality assurance to marking, the scope of photonics is wide-reaching. Specifically, the use of lasers and machine vision in oral solid dose (OSD) manufacturing is revolutionizing functionality, security and speed while reducing costs and boosting efficiency.
In certain regions of the world, a growing problem concerns medication quality, stemming from poor manufacturing processes. For example, drugs manufactured with a lower dosage of active ingredients than approved by regulators is a dangerous situation that can lead to patients not receiving a medication's full benefit. Worst-case black market scenarios…

The first thing to remember is that Analytical Chemists (ACs) and Biochemists (BCs) see the world differently. Analytical types have always worked with inferential tests: color changes, odors, precipitates (for classes of elements) and felt comfortable using “clues” to deduce the answer. Biochemists, especially in the drug industry, are always attempting to be specific. If a reaction is proceeding, what is being used and produced; if it has ended, what is left in the reactor and what was produced.
They want to know the exact composition of the “soup.” So when PAT was broached to the ACs, for example, blend uniformity testing, we felt fine just seeing that the spectra stopped changing, implying that the mixing was complete. BCs tend…

The biopharmaceutical industry long has recognized that nutrient feed control is crucial to process development lead-times and to manufacturing quality, yield and cost. Real-time measurement of physical parameters such as pH and dissolved oxygen is insufficient to achieve dynamic feed control. Instead, companies still depend upon predetermined nutrient regimes or periodic extractive sampling and offline analysis, resulting in suboptimal conditions for cell culture, process delays and risk of infection.
The majority of biopharmaceutical processes use a fed-batch nutrient-feeding regime to maintain cell culture activity. Current fed-batch processes rely on predetermined feeding protocols based on nutrient requirement estimates or infrequent…

For the first time in a long time, the Internet is abuzz with something that might actually eclipse the Internet in terms of impact on the world.

Buzzwords get a bad rap. This is mostly due to operator error. Sometimes really valid concepts get haphazardly tossed around so frequently by people who don’t fully understand them that the actual concept starts getting muddled. But this shouldn’t always devalue the initial idea.
The “Internet of Things” is a good example. There are so many articles casually using the acronym “IoT” that it has become difficult to find a basic discussion of the concept.
In its most simplistic form, the IoT is a network of physical devices embedded with sensors and electronics, where all the devices speak to each other using the existing Internet infrastructure. The INDUSTRIAL Internet of Things (IIoT) is simply the Internet of Things when…

For the first time in a long time, the Internet is abuzz with something that might actually eclipse the Internet in terms of impact on the world.

Buzzwords get a bad rap. This is mostly due to operator error. Sometimes really valid concepts get haphazardly tossed around so frequently by people who don’t fully understand them that the actual concept starts getting muddled. But this shouldn’t always devalue the initial idea.
The “Internet of Things” is a good example. There are so many articles casually using the acronym “IoT” that it has become difficult to find a basic discussion of the concept.
In its most simplistic form, the IoT is a network of physical devices embedded with sensors and electronics, where all the devices speak to each other using the existing Internet infrastructure. The INDUSTRIAL Internet of Things (IIoT) is simply the Internet of Things when…

Across major geographies, under-budget projects are the exception rather than the rule

Globalization and disruptive technological advancements, such as virtualization, cloud and big data, are continually altering the industrial landscape. To succeed, innovative companies must re-envision where and how they do business so the right resources are applied regardless of their location. In the past decade, concepts like virtual teaming and multi-office execution began to play major roles in the operating strategies of engineering, procurement and construction (EPC) and global engineering firms. Offshoring is no longer isolated to manufacturing, data processing and call-center positions, as a growing number of firms move engineering, design and development work overseas as well.
IN PURSUIT OF COSTS TO CUTCost reduction is a…

The roots of product lifecycle management and how PLM can help chemical companies today

Product Lifecycle Management (PLM) originated in the automotive industry, and as a breed of IT application it is still mainly associated with discrete manufacturing. Having started with the scope of product data management for the development phase of a product lifecycle, the reach of the technology has evolved to cover the full product lifecycle — and close the loop by supporting the exploitation of field experience to drive front end innovation (for example, Oracle seeks to reinforce this by referring to ‘Product Value Chain Management’).The PLM technologies designed for discrete manufacturing industries deliver enormous benefit in product development scenarios involving high numbers of parts with their relationships defined by a…

The roots of product lifecycle management and how PLM can help chemical companies today

Product Lifecycle Management (PLM) originated in the automotive industry, and as a breed of IT application it is still mainly associated with discrete manufacturing. Having started with the scope of product data management for the development phase of a product lifecycle, the reach of the technology has evolved to cover the full product lifecycle — and close the loop by supporting the exploitation of field experience to drive front end innovation (for example, Oracle seeks to reinforce this by referring to ‘Product Value Chain Management’).The PLM technologies designed for discrete manufacturing industries deliver enormous benefit in product development scenarios involving high numbers of parts with their relationships defined by a…

BMS-663068 is the first investigational antiretroviral designed to prevent HIV attachment to and entry into CD4+ T cells

Bristol-Myers Squibb announced the FDA has granted Breakthrough Therapy Designation to the investigational compound BMS-663068 when used in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in heavily treatment-experienced adult patients.
The designation is based on data from the Phase IIb clinical study comparing BMS-663068 to a boosted protease inhibitor (Reyataz (atazanavir sulfate) and ritonavir) in treatment-experienced patients, with a treatment backbone across all arms of raltegravir, in addition to tenofovir disoproxil fumarate, BMS says. A Phase III trial in heavily treatment-experienced patients began in February 2015 and is ongoing.
“We are now 30-plus years into the AIDS epidemic, and…

The release of volatile organic compounds into the atmosphere is coming under intense scrutiny

With an ever-increasing number of processing plants coming on stream worldwide to keep up with the rapidly expanding pharmaceutical and biotechnology industries, the focus on the release of volatile organic compounds (VOCs) into the atmosphere is coming under intense scrutiny by environmental authorities.VOC is the common descriptor for a wide variety of hydrocarbon-containing chemicals. They are numerous, varied and ubiquitous, and the risks associated with them are aggravated by the fact that hazardous concentrations are usually very low and the health issues they can cause can be accumulative and slow to develop. The release of VOCs from industrial processes not only poses a direct potential hazard to human health, but their release…

There are a few special considerations for mapping humidity: calibration and sensor density/placement.

Editor's note: this is a 60-second version of the original article. To read the full length feature, click the link at the end of the brief.
It has become more common to validate humidity as well as temperature in controlled environments in order to meet GxP requirements. Typically we use the same methods for humidity mapping as for temperature, however, there are a few special considerations for mapping humidity.
1) CalibrationVerify that calibration certificates are available for the humidity sensors, and that each sensor was within its calibration interval at the time of use.
2) Sensor Density & PlacementThe simplest practice is to use the same number of humidity and temperature sensors. If fewer humidity sensors must be used, it is…

There are a few special considerations for mapping humidity: calibration and sensor density/placement.

Editor's note: this is a 60-second version of the original article. To read the full length feature, click the link at the end of the brief.
It has become more common to validate humidity as well as temperature in controlled environments in order to meet GxP requirements. Typically we use the same methods for humidity mapping as for temperature, however, there are a few special considerations for mapping humidity.
1) CalibrationVerify that calibration certificates are available for the humidity sensors, and that each sensor was within its calibration interval at the time of use.
2) Sensor Density & PlacementThe simplest practice is to use the same number of humidity and temperature sensors. If fewer humidity sensors must be used, it is…

The first thing to remember is that Analytical Chemists (ACs) and Biochemists (BCs) see the world differently. Analytical types have always worked with inferential tests: color changes, odors, precipitates (for classes of elements) and felt comfortable using “clues” to deduce the answer. Biochemists, especially in the drug industry, are always attempting to be specific. If a reaction is proceeding, what is being used and produced; if it has ended, what is left in the reactor and what was produced.
They want to know the exact composition of the “soup.” So when PAT was broached to the ACs, for example, blend uniformity testing, we felt fine just seeing that the spectra stopped changing, implying that the mixing was complete. BCs tend…

From tablet marking to quality assurance, lasers and machine vision are boosting functionality and efficiency.

Editor's note: this is a 60-second version of the original article. To read the full length feature, click the link at the end of the brief.
In the multidisciplinary pharma industry, photonics plays an increasingly crucial role in the manufacturing process. From quality assurance to marking, the scope of photonics is wide-reaching. Specifically, the use of lasers and machine vision in oral solid dose (OSD) manufacturing is revolutionizing functionality, security and speed while reducing costs and boosting efficiency.
In certain regions of the world, a growing problem concerns medication quality, stemming from poor manufacturing processes. When medicine is inexpensive in less-developed countries but moves through the gray market to be…

A well-designed, reliable raw material storage and conveyance environment can make or break a pharmaceutical manufacturing environment. Raw material storage and conveyance is fundamental to quality assurance and profitability. Increasingly, this environment also has become integral to the rigorous regulatory requirements for tracking and tracing products throughout the supply chain. To meet quality and standardization objectives, a design solution must be based on an overview of the entire process from delivery of raw materials to the manufacturing site to delivery of product ingredients to the manufacturing line. The correct design basis is predicated, particularly, on an understanding of raw material characteristics and facility…

Each application requires a different level of air quality and a different combination of air treatment to meet the needed specs

In the pharmaceutical industry, compressed air is used for a number of production and packaging applications, including blowing off and drying bottles prior to filling, conveying pills, providing air for pneumatically controlled valves and cylinders, as well as breathing air systems.
Each of these applications requires a different level of air quality and a different combination of air treatment to meet the needed quality. Because the uses of compressed air within the industry vary so greatly, there is no set standard in place that every process must adhere to.
While the FDA may not have issued a directive for compressed air quality in the pharmaceutical industry, there is still a resource available to help select appropriate air treatment…

Across major geographies, under-budget projects are the exception rather than the rule

Globalization and disruptive technological advancements, such as virtualization, cloud and big data, are continually altering the industrial landscape. To succeed, innovative companies must re-envision where and how they do business so the right resources are applied regardless of their location. In the past decade, concepts like virtual teaming and multi-office execution began to play major roles in the operating strategies of engineering, procurement and construction (EPC) and global engineering firms. Offshoring is no longer isolated to manufacturing, data processing and call-center positions, as a growing number of firms move engineering, design and development work overseas as well.
IN PURSUIT OF COSTS TO CUTCost reduction is a…

Almost anyone can recognize the practicality associated with the concept of modularity. To the many engineers who busy themselves designing, engineering and constructing complex pharma processing systems, the idea of managing such complexity by breaking it down into standardized subsystems and components is a well understood and pragmatic approach to system design. According to Festo, such is the case with automation and control. Modular systems, say Festo, speed up the design and configuration of automated processes, lower overall costs, and make a process like water filtration more flexible and therefore better at adapting to new operational requirements and responsive to market demands.
"This approach represents a fundamental shift in…

The acquisition includes 19 solid-oral dosage products and three oral suspension products

ANI Pharmaceuticals Inc. has acquired 22 previously marketed generic drug products from Teva Pharmaceuticals for $25 million in cash and a percentage of future gross profits from product sales. The acquisition includes 19 solid-oral dosage products and three oral suspension products.
ANI will initially focus to tech transfer four products that qualify as CBE30 filings into ANI’s two manufacturing facilities; these four products have a combined trailing 12-month market value of $210 million, according to IMS Health. The total market value for the 22 products is $650 million on a trailing twelve month basis, per IMS Health. The acquisition is being funded through cash on hand.
Arthur S. Przybyl, President and CEO of ANI Pharmaceuticals,…

BMS-663068 is the first investigational antiretroviral designed to prevent HIV attachment to and entry into CD4+ T cells

Bristol-Myers Squibb announced the FDA has granted Breakthrough Therapy Designation to the investigational compound BMS-663068 when used in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in heavily treatment-experienced adult patients.
The designation is based on data from the Phase IIb clinical study comparing BMS-663068 to a boosted protease inhibitor (Reyataz (atazanavir sulfate) and ritonavir) in treatment-experienced patients, with a treatment backbone across all arms of raltegravir, in addition to tenofovir disoproxil fumarate, BMS says. A Phase III trial in heavily treatment-experienced patients began in February 2015 and is ongoing.
“We are now 30-plus years into the AIDS epidemic, and…

The acquisition includes 19 solid-oral dosage products and three oral suspension products

ANI Pharmaceuticals Inc. has acquired 22 previously marketed generic drug products from Teva Pharmaceuticals for $25 million in cash and a percentage of future gross profits from product sales. The acquisition includes 19 solid-oral dosage products and three oral suspension products.
ANI will initially focus to tech transfer four products that qualify as CBE30 filings into ANI’s two manufacturing facilities; these four products have a combined trailing 12-month market value of $210 million, according to IMS Health. The total market value for the 22 products is $650 million on a trailing twelve month basis, per IMS Health. The acquisition is being funded through cash on hand.
Arthur S. Przybyl, President and CEO of ANI Pharmaceuticals,…

Mylan's current acquisition target Perrigo announced it is buying German pharmacy company, Naturwohl Pharma.

Mylan's current acquisition target Perrigo announced it is buying German pharmacy company, Naturwohl Pharma.
Perrigo did not disclose terms of the deal for Naturwohl and its leading German dietary supplement brand, Yokebe. The transaction has been approved by the boards of both companies.
Perrigo CEO Joseph Papa anticipates the deal will help Perrigo capture a greater share of the $30 billion European over-the-counter market.
Caught in a takeover triangle, Perrigo rejected an unsolicited takeover bid from Mylan in late April, about the same time Mylan rejected an offer of $40 billion from Teva.
Read the USA Today article

Respond fully to allegations, experts say; if youre considering blowing the whistle, be sure the noncompliance is serious enough to threaten product integrity.

For years, FDA has warned industry that “employees and former employees” would be critical in examining questions of cGMP compliance and corporate data integrity. A groundbreaking legal decision has since borne out this statement, emphasizing the importance of compliance and data integrity in preventing legal liability, and even criminal charges against noncompliant companies and managers.

Last October, former GlaxoSmithKline quality assurance manager Cheryl Eckard received a $96-million settlement after suing her former employer under the False Claims Act (FCA). Her legal complaint, which she had first brought to the FDA, had documented numerous cGMP noncompliance problems, including major data integrity issues, at the company’s former Cidra facility in Puerto Rico.

In addition to such flagrant problems as product mixups, she cited unsigned, undated and missing validation, investigation and change control documents, and SOP’s in need of revision. The company did not appeal, making Eckard’s case the first pharmaceutical whistleblowing lawsuit to invoke cGMP’s and succeed.

“Companies are now on notice that cGMP violations are open to the scrutiny of whistleblowers,” says Neil Getnick, of Getnick and Getnick Law (New York, N.Y.), who, with colleague Lesley Ann Skillen, represented Eckard.

Today, at least one pharma cGMP whistleblower case is reportedly under seal, involving compliance and the use of computerized quality controls, at a generic drug manufacturer in the northeastern U.S. Theoretically, whistleblowing cases can be brought against an employer based on the FCA, Sarbanes-Oxley reporting requirements, or evolving SEC regulations (Box). Experts agree that, whatever side you’re on, due diligence is key.

This article will briefly examine expert opinion on the potential for cGMP whistleblower cases, from both the employee’s and the corporate manager’s perspectives, touch very lightly on the gray area between chronic noncompliance and criminal fraud, and highlight the importance of data integrity to overall compliance efforts.

Untested FrameworkWhen Cheryl Eckard first approached them, it was the first time that Getnick and Skillen had considered a False Claims Act suit based on cGMP noncompliance. “This was a challenge, as Medicare and Medicaid statutes do not speak directly to cGMP compliance . . . the legal framework was untested,” Getnick says.

Ken Nolan, founding partner of Nolan and Auerbach, P.A. (Philadelphia), has successfully represented qui tam whistleblowers regarding off-label marketing. He had received inquiries from other would-be cGMP whistleblowers in the past. However, he notes, their cases were either too difficult to prove, or cited technical noncompliance issues that did not directly threaten product integrity. In addition, Nolan notes, the U.S. government has been reluctant to get involved unless egregious manufacturing deficiencies are involved that clearly put patients at risk, he says.

However, these issues are also most frequently found in 483’s and inspection reports. Is there a boundary between chronic noncompliance and intentional fraud? Consultant John Avellanet, founder of Cerulean Associates, an FDA compliance consulting firm, sees a continuum, from ignorance to sloppiness to fraud, quoting Eugene Thirolf, head of the U.S. Department of Justice’s Office of Consumer Litigation. “Noncompliance always comes down to two reasons: ignorance or financial pressures.” “It’s the pressure to cut corners that causes most intentional fraud,” Avellanet says.

As Nolan explains, the False Claims Act only affects those who knowingly present a fraudulent claim, leaving simple negligence or innocent mistakes out. However, to suggest intent, he says, one must only establish that the defendant had actual knowledge of the information and either acted in deliberate ignorance, or reckless disregard of the information’s truth or falsity.

“FCA could apply in situations that show substantial gross negligence, or, in the plain language of the cGMP code itself, ‘reckless disregard,’ ” Nolan says.

This allows the Act to reach beyond the “head-in-the-sand” type manager, who may hide behind the fact that he or she was not personally aware that manufacturing or cGMP testing problems were made to appear okay in written responses to the Government. In addition, says Nolan, the criticality of the data is a decisive factor. If a company makes false statements about the sufficiency of its assay testing, one must ask: Would the lack of proper assay testing likely lead to a material deficiency in the product, or would such a deficiency be entirely speculative?

Once a pharma company submits paperwork that is false, that materially affects the integrity of the product, and it can be shown that the submission was not due to an oversight, the company faces liability.

There is no simple “litmus test” for determining whether cGMP violations are sufficiently serious to attract FCA liability, says Skillen. However, she notes that GMP non-compliance, if chronic and serious, will often amount to fraud on the government, which pays for drugs based on manufacturers’ claims of quality, strength, identity and purity as set forth in the NDA. “Without that assurance, the government is not getting what it paid for,” she says.

In the GSK whistleblowing case, Cheryl Eckard had pursued internal corporate communication channels before seeking legal help. Meetings and calls to senior managers, and a call to the CEO, met with insufficient, or no, response, her complaint says. It was this lack of response that may have helped build her case. Management’s involvement in the false record or statements, either through gross negligence or knowledge, is sufficient to establish corporate liability, says Nolan.

A mix of feature articles and current new stories that are critical to staying up-to-date on the industry, delivered to your inbox. Choose from an assortment of different topics and frequencies. Subscribe Today.